The compound of the invention referred herein by its generic name Clopidogrel bisulfate corresponds to the empirical formula C16H16ClNO2S.H2SO4 and has a molecular weight 419.9. Chemically it is methyl (+)-(S)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1), having the following structural formula

Clopidogrel is an inhibitor of platelet aggregation and is marketed as an antianginal agent, antiplatelet agent and is found to decrease morbid events in people with established atherosclerotic cardiovascular disease and cerebrovascular diseases.
The therapeutic application of Clopidogrel as blood-platelet aggregation inhibiting agents and antithrombotic agent and its preparation is disclosed in U.S. Pat. No. 4,529,596.
U.S. Pat. No. 4,847,265 describes the process for the preparation of the hydrogen sulfate salt of clopidogrel.
Various other strategies to prepare Clopidogrel are disclosed in WO 98/51681, WO 98/51682, WO 98/51689, WO 99/18110, U.S. Pat. Nos. 5,036,156, 5,132,435, 5,139,170, 5,204,469 and 6,080,875.
We have recently disclosed novel processes for the manufacture of (S)-(+)-Clopidogrel bisulfate (Indian Patent Applications 335/MUM/2001 and 630/MUM/2001).
U.S. Pat. No. 4,847,265 discloses that the dextrorotatory enantiomer of formula (I) of Clopidogrel has an excellent antiagregant platelet activity, whereas the corresponding levorotatory enantiomer of (I) is less tolerated of the two enantiomers and is less active. U.S. Pat. No. 4,847,265 relates to the dextrorotatory enantiomer and its pharmaceutically acceptable salts with platelet aggregation inhibiting activity. However, the precision of determination of laevoenantiomer in dextrorotatory enantiomer was not less than 4%, implying thereby that the method used by the inventors cannot distinguish precisely a sample of S:R ratio 96:4 from a sample having the two enantiomers in the ratio 99.5:0.5 (refer page 5, line 35-50, U.S. Pat. No. 4,847,265). Current regulatory requirements, however, require a high chiral purity (ee not less than 99%) for chiral drugs.
Subsequently filed Patent Application WO 99/65915 (U.S. Pat. No. 6,429,210) titled “Polymorphic Clopidogrel hydrogensulfate form”, which is herein incorporated by reference, discloses the existence of a specific polymorphic Form II of the hydrogen sulfate of (S)-(+)-Clopidogrel (m.p.=176±3° C.). It is also disclosed in this patent application that the earlier processes described in the U.S. Pat. No. 4,847,265 gives Form I (m.p. 184±3° C.). These two crystalline polymorphic forms I and II differed in their stability, physical properties, spectral characteristics and their method of preparation, however, both the polymorphs have similar bioavailability, as shown in their bioequivalence in healthy human volunteers.
Although U.S. Pat. No. 4,847,265 reports the formation of (S)-(+)-Clopidogrel bisulfate salt with m.p. 184° C., it was disclosed as Form I only in patent application WO 99/65915. However, a reproducible and consistent method for the preparation of Form I with chirally pure material (ee>99%) was in doubt since chiral purity of the material (Clopidogrel bisulfate) with m.p. 184±3° C., disclosed in U.S. Pat. No. 4,847,265 was not precisely known (degree of imprecision 4% as discussed above.).
In fact, we have observed that formation of Form I of (S)-(+)-Clopidogrel bisulfate with chiral purity>99% ee) is inconsistent and difficult to reproduce using the procedures reported in U.S. Pat. No. 4,847,265 and WO 99/65915 whereas the formation of Form II is extremely facile and consistent with optically pure (S)-(+)-Clopidogrel free base.
Therefore it is very essential to find an alternate polymorphic form which can be consistently produced with high optical purity (ee>99%).
In the present invention, we wish to disclose that formation of form I of Clopidogrel bisulfate is quite reproducible and consistent, if the optical purity is low (S:R=96:4) as reported in U.S. Pat. No. 4,847,265. Therefore, it is imperative to prepare another polymorph of Clopidogrel bisulfate with high optical purity (>99% ee). The present invention describes a new amorphous form of (S)-(+)-Clopidogrel bisulfate having optical purity greater than 99% (ee).
Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Konno T., Chem. Pharm. Bull., 1990; 38: 2003-2007). For some therapeutic indications, one bioavailability pattern may be favoured over another. Therefore, it is desirable to have amorphous forms of drugs and a highly reproducible processes for their preparation.